Project Summary Important roles for microbes and antimicrobial defenses in the pathogenesis of Alzheimer's disease (AD) have been postulated and investigated for at least six decades, beginning with Sjgren in 1952. The proliferation of large, multiomic Alzheimer's disease (AD) focused data sets offer unprecedented and unbiased views of the molecular networks that underlie AD. Through the direct examination of viral RNA and DNA sequences in next generation sequencing data, we have observed the presence of many viral species in the aging brain, and linked multiple viral species with AD biology, including regulation of AD genetic risk networks, AD gene expression changes, and association with clinical dementia rating and neuropathology burden. Together, these findings indicate that multiple viruses are at increased abundance in AD, across multiple brain tissues, with prominent roles for Roseoloviruses HHV-6A, HHV-6B and HHV-7 (Readhead et al, In Press, Neuron). A key challenge for the ?pathogen hypothesis? of AD, is to understand whether such findings represent a causal contribution, or reflect opportunistic passengers of a general neurodegenerative process. HHV-6A, HHV- 6B, and HHV-7 are remarkable among viruses for their capacity to integrate into subtelomeric regions of host cell chromosomes, and recent studies have shown that inherited, chromosomally integrated HHV-6 (ciHHV-6) is present in approximately 1% of the US and UK population. This offers the opportunity for a natural experiment, where we can potentially link an inherited viral factor, with AD risk, and better address the plausibility of whether viruses such as these, are capable of causally contributing to the onset and/or progression of AD, at least under some circumstances. Our hypothesis is that iciHHV-6 will emerge as a risk factor for developing AD. This is a valuable hypothesis to evaluate, as: (1) it represents an opportunity to identify a novel AD patient subpopulation, which could inform subsequent translational studies, and (2) studying these viruses in an inherited form, will enable us to better understand the plausibility of a causal role for viruses in AD. Our preliminary studies of whole genome sequences (WGS) and whole exome sequences (WES) generated on the individuals in the cohort described above, have shown some evidence of increased rates of iciHHV-6 among individuals with AD, however the cohort size is only modestly powered to detect differences in rare inherited variations like iciHHV-6. The goal of this proposed study, is to combine available genetic data from the Alzheimer's Disease Sequencing Project and Accelerating Medical Partnerships in Alzheimer's disease to identify instances of iciHHV-6 within this cohort, and perform a genetic association study that evaluates whether iciHHV-6 is a risk factor for AD, or AD related traits.